a general method for the synthesis of tetramic acid derivatives

1356 J. Org. Chem. 1988,53, 1356-1364

dihydroisoflavone (7e). From 0.5 g of acid 3e, a mixture of 6e and 7e was obtained. Separation by silica gel chromatography resulted in 90 mg (24%) of 6e and 210 mg (49%) of 7e.

6e: mp 90-92 "C; IR 1630,1600,1570 cm-'; GC/MS (70 eV), m/e (relative intensity) 266 (M', loo), 235 (38), 234 (lo), 159 (321, 135 (44); 'H NMR (CDC13) 6 2.4 (s, 3 H), 3.8 (s, 3 H), 7.0-7.6 (m, 8 H); 13C NMR (CDC1,) 6 191.1, 163.2, 156.6, 153.28 131.7, 130.6, 128.5, 126.2, 123.9, 123.5, 121.1, 120.6, 117.7, 111.2, 110.4, 55.4, 14.3.

Anal. Calcd for C13H1403: C, 76.69; H, 5.26. Found: C, 76.67; H, 5.32.

7e: mp 110-111 "C; IR 1850,1690,1605 cm-'; GC/MS (70 eV), m/e (relative intensity) 310 (M', 3), 266 (25), 251 (43), 235 (100); lH NMR (CDC13) 6 1.4 (s, 3 H), 3.7 (s, 3 H), 6.9-8.0 (m, 8 H); 13C NMR (CDC13) 6 186.0, 169.2,158.0,155.4,136.8, 130.6,128.8,126.9, 126.6, 122.0, 121.4, 118.9, 118.5, 110.6, 91.0, 84.0, 55.6 18.0.

#?-Lactone of 2-Carboxy-3-hydroxy-2-methyl-2',4',7-tri- methoxy-2,3-dihydroisoflavone (7f). A 0.48-g (57%) portion of 7f was obtained from 1 g of 3f: mp >135 "C dec; IR 1850,1685, 1610 cm-'; GC/MS (70 eV), m/e (relative intensity) 326 (M+ - COz, 39), 312 (8), 311 (41), 295 (100); 'H NMR (CDCl,) 6 1.5 (s, 3 H), 3.6 (s, 3 H), 3.8 (s, 3 H), 3.9 (s, 3 H), 6.45-6.75 (m, 4 H), 7.4 (d, 1 H), 7.9 (d, 1 H); 13C NMR (CDCl,) 6 184.5, 169.5 166.6, 161.8, 160.1, 156.3, 130.6, 127.6, 114.7, 112.3, 112.2, 104.8, 101.3, 98.9, 90.9, 83.6, 55.8, 55.6, 55.4, 18.1.

Anal. Calcd for CmH1807: C, 64.86; H, 4.86. Found C, 65.35; H, 5.20. 6-Methyl-l-phenyl-2-oxa-3,4-benzobicyclo[ 3.2.01 heptan-7-

one (10). A 0.5-g (1.87 mmol) portion of [(o-propenylphen- oxy)phenyl]acetic acid was refluxed with 2.0 g (24 mmol) of sodium acetate and 15 mL (159 mmol) of acetic anhydride for 4 h. The reaction mixture was poured into a cold dilute aqueous sodium of hydroxide solution and extracted with ether. The ether extract was dried over anhydrous magnesium sulfate and then evaporated to 0.5 g (90%) of 9: IR, 1760,1680,1605,1590, cm-'; GC/MS (70 eV), m/e (relative intensity) 292 (M+, 13), 250 (M' - 42, 78), 235 (ll), 222 (27), 221 (47), 205 (59), 194 (29), 178 (22), 165 (40), 42 (100); 'H NMR (CDC13) 6 1.9 ( 8 , 3 H), 2.15 (s, 3 H), 3.8 (s, 1 H), 6.8-7.6 (m, 10 H); 13C NMR (CDCI,) s' 166.8, 162.1, 137.5, 136.2, 134.1, 128.7, 128.5, 128.2, 127.9, 125.6, 124.4, 120.6, 111.7, 93.7, 55.3, 20.6, 12.3.

Compound 9 was treated with a 50% aqueous potassium hydroxide solution containing methanol. The methanol was removed under reduced pressure and the aqueous residue extracted with ether. Upon drying the ether over anhydrous magnesium sulfate, and the ether was evaporated to yield 0.3 g (64%) of 10. The mp and IR and 'H and 13C NMR spectra were identical with those previously reported.lf

Cyclization of 3d and 3e Using Perkin Reaction Condi- tions. A 0.5-g portion of 3d was refluxed with 1.5 equiv of acetic anhydride and 2.0 equiv of sodium acetate in 30 mL of benzene for 24 h. The reaction mixture was cooled and filtered and an IR spectrum of the concentrated filtrate revealed a strong @- lactone peak at 1850 cm-'. Rotary chromatography of the filtrate resulted in 0.1 g of 6d (25%) and 0.08 g of 7d (17%).

A 0.1-g portion of 3e was treated as described above. An IR spectrum of an aliquot of the reaction mixture revealed a strong @-lactone peak a t 1850 cm-'. Thin layer chromatography revealed two spots with the same R values as characterized above for 6e and 7e. Preparative thin iayer chromatography gave a trace of 6e and 7e, which were identified by IR and GC/MS.

General Procedure for Decarboxylation of 8-Lactones 7d-f. A sample of the @-lactone was placed in a melting point capillary tube and heated in a melting point apparatus. When the temperature reached 135-140 "C, small bubbles began to appear. The temperature was kept at 150 "C for 5 h. The tube was broken and the contents were recovered for analysis.

2-Methylisoflavone (8d). This isoflavone was recovered as an oil: IR 1650 cm-'; 'H NMR (CDCI,) 6 2.30 (s, 3), 7.25-8.25 (m, 9 H). 2-Methyl-2'-methoxyisoflavone (Se). This isoflavone was

also recovered as an oil: IR 1645, 1600, 1575 cm-'; 'H NMR (CDC1,) 6 2.2 (s, 3 H), 3.8 (s, 3 H), 7.0-8.2 (m, 8 H). 2-Methyl-2',4',7-trimethoxyisoflavone ( S f ) . This isoflavone

was recovered as a crystalline solid mp 185-187 "C; IR 1625,1610 cm-'; 'H NMR (CDCl,) 6 2.2 (s, 3 H), 3.75 (s, 3 H), 3.85 (s, 3 H), 3.90 (s, 3 H), 6.6 (m, 2 H), 6.9 (m, 2 H), 7.1 (m, 1 H), 8.1 (d, 1 H); 13C NMR (CDCl,) 6 176.2, 163.7, 163.5, 160.9, 158.3, 157.6, 132.4, 127.7, 119.4, 117.2, 114.7, 113.8, 104.7,99.9, 99.0, 55.7, 55.6, 55.4, 19.2.

Anal. Calcd for C19H1805: C, 69.94; H, 5.52. Found C, 69.86; H, 5.63.

Acknowledgment. We are grateful to the Robert A. Welch Foundation for support of this work.

Registry No. la, 34082-43-4; lb, 6706-92-9; IC, 82362-01-4; 2a, 34589-99-6; 2b, 107943-61-3; 2c, 95281-05-3; 3a, 113180-51-1;

3f, 113180-54-4; 6a, 6454-01-9; 6b, 113180-55-5; 6d, 18703-72-5; 6e, 93321-78-9; 7d, 113180-56-6; 7e, 113180-57-7; 7f, 113180-58-8; 8a, 574-12-9; 8b, 7622-32-4; 8c, 7678-84-4; 8d, 24258-66-0; 8e,

H0,CCH(Ph)OC6H4CH=CHCH,, 99477-28-8; MeCHBrC02- CHzMe, 535-11-5; 2,2'-dihydroxy-4,4'-dimethoxybenzil, 6706-94-1; ethyl a-bromoacetate, 105-36-2.

3b, 103031-10-3; 3c, 103206-86-6; 3d, 113180-52-2; 3e, 113180-53-3;

113180-59-9; Sf, 70387-01-8; 9, 113218-61-4; 10, 99477-35-7; 2-

A General Method for the Synthesis of Tetramic Acid Derivatives

Philip DeShong,* Joseph A. Cipollina,+ and Nancy K. Lowmasted Department of Chemistry and Biochemistry, The University of Maryland, College Park, Maryland 20742

Received October 3, 1987

Fragmentation of 2,5-disubstituted isoxazolium salts resulted in the formation of highly functionalized @-keto amide derivatives. Subsequent base-catalyzed cyclization afforded 3-acyltetramic acid derivatives similar to the tetramic acid moieties found in tirandamycin A/B and streptolydigin. The scope and limitations of this methodology for the total synthesis of naturally occurring tetramic acid antibiotics is discussed.

The dienoyl tetramic acids tirandamycin A (1) and B (2)' streptolydigin (3)2 and ikarugamycin (4)3 are representative examdes of the structurally diverse family of

tetramic acid antibiotics. The common feature of these natural products is the 2,4-pyrrolidinedione or tetramic

Taken in part from the Masters Thesis of Joseph A. Cipollina, The Pennsylvania State University, 1987. Present address: Bris- tol-Myers Company; 5 Research Parkway; P. 0. Box 5100; Walling- ford, CT 06492-7660.

*Taken in part from the Masters Thesis of Nancy K. Lowmaster, The Pennsylvania State University, 1987. Present address: De- partment of Chemistry, Allegheny College, Meadville, PA.

0022-3263/88/1953-1356$01.50/0 0

(1) MacKellar, F. A.; Grosic, M. F.; Olson, E. C.; Wnuk, R. J.; Branfman, A. R.; Rinehart, K. L., Jr. J. Am. Chem. SOC. 1971,93,4943. Duchamp, D. J.; Branfman, A. R.; Button, A. C.; Rinehart, K. L., Jr. Ibid. 1973, 95, 4077.

(2) Rinehart, K. L., Jr.; Beck, J. R.; Epstein, W. W.; Spicer, L. D. J. Am. Chem. SOC. 1963,85,4035. Rinehart, K. L., Jr.; Borders, D. B. Ibid 1963.85. 4037. Rinehart. K. L.. Jr.; Beck, J. R.; Borders, D. B.; Kinstle, T. H.; Kraus, D. Ibid. 1963,85,4038. Duchamp, D. J.; Branfman, A. R.; Button, A. C.; Rinehart, K. L., Jr. Ibid. 1973, 95, 4077.

1988 American Chemical Society

Synthesis of Tetramic Acid Derivatives

acid moiety (5). We4 and others5-" have developed a variety of general

strategies for the total synthesis of tetramic acid derivatives. A major focus of these studies has been the evolution of methodologies for the preparation of highly functionalized tetramic acid reagents. As depicted by structures 1-4, it is necessary to synthesize tetramic acid moieties

J. Org. Chem., Vol. 53, No. 7, 1988 1357

Scheme I

R,,,&$O

Me&-- Me Me Me Me

tirandamycin A/B A ( l ) : R = C H 3 B(2): R = CH20H

0

streptolydig in 3

ikarugamycin 4

having (1) a (po1y)enoyl functionality a t C-3 and (2) sub- stituents at N-1 and C-5 of the heterocyclic nucleus. Once the tetramic acid has been introduced, subsequent trans- formations of the molecule are restricted due to the sen- sitivity of this functional group; therefore, it is prudent to introduce the tetramic acid at the final stages of the total synthesis of the antibiotics.

A potential solution to this dilemma is outlined in Scheme I. The retrosynthetic strategy envisioned condensation of an aldehyde with the anion (or dianion) of phosphonate 7 to provide enoyl tetramic acid 6. This

(3) Ito, S.; Hirata, Y. Tetrahedron Let t . 1972, 2557. (4) (a) For a preliminary communication concerning this topic, see:

DeShong, P.; Lowmaster, N. E.; Baralt, 0. J. Org. Chem. 1983,48,1149. (b) See also: DeShong, P.; Ramesh, S.; Elango, V.; Perez, J. J. J. Am. Chem. SOC. 1985, 107, 5219 and references cited therein.

(5) (a) Schlessinger, R. H.; Bebernitz, G. R. J. Org. Chem. 1985, 50, 1344. (b) Schlessinger, R. H.; Bebernitz, G. R.; Lin, P.; Poss, A. J. J. Am. Chem. SOC. 1985, 107, 1777.

(6) (a) Boeckman, R. K., Jr.; Thomas, A. J. J. Org. Chem. 1982, 47, 2823. (b) Boeckman, R. K., Jr.; Starrett, J. E., Jr.; Nickell, D. G.; Sum, P.-E. J. Am. Chem. SOC. 1986,108,5549. (c) Boeckman, R. K., Jr.; Perni, R. B. J. Org. Chem. 1986,51,5486. (d) Boeckman, R. K., Jr.; Potenza, J. C.; Enholm, E. J. Ibid. 1987, 52, 472.

(7) (a) Ireland, R. E.; Wuta, P. G. M.; Ernst, B. J. Am. Chem. SOC. 1981,103,3205. (b) Ireland, R. E.; Wardle, R. B. J. Org. Chem. 1987,52, 1780.

(8) Jones, R. C. F.; Peterson, G. E. Tetrahedron Lett. 1983,24,4751, 4755.

(9) Lee, V. J.; Branfman, A. R.; Herrin;T. R.; Rinehart, K. L., Jr. J. Am. Chem. SOC. 1978,100,4225. Cartwright, D.; Lee, V. J.; Rinehart, K. L., Jr. Ibid. 1978, 100, 4237.

(10) Neukom, C.; Richardson, D. P.; Myerson, J. H.; Bartlett, P. A. J. Am. Chem. SOC. 1986,108, 5559.

(11) (a) Martin, S. F.; Gluchowski, C.; Campbell, C. L.; Chapman, R. C. J. Org. Chem. 1984, 49, 2512. (b) Ziegler, F. E.; Thottathil, J. K. Tetrahedron Lett. 1981,22,4883. Ziegler, F. E.; Wester, R. T. Ibid. 1984, 25,617. (c) Matsuo, K.; Kimura, M.; Kinuta, T.; Takai, N.; Tanaka, K. Chem. Pharm. Bull. 1984, 32, 4197 and references cited therein. (d) Capraro, H.-G.; Winkler, T.; Martin, P. Helu. Chim. Acta 1983, 66, 362. (e) Kelly, T. R.; Chandrakumar, N. S.; Cutting, J. D.; Goehring, R. R.; Weibel, F. R. Tetrahedron Let t . 1985, 26, 2173. (f) Danishefsky, S.; Harvey, D. F. J. Am. Chem. SOC. 1985, 107, 6647.

k' 'R'

6 7

\ Q R'

6

10

Scheme I1 Me

NBS,. C C k . A, (PhC0)202

80 Y h

; f P(oEt)2

10 +

12

approach was especially appealing because the tetramic acid moiety could be delivered intact at an advanced stage of a synthesis while avoiding the need for protecting groups. Secondly, acyl phosphonate anions are known to condense readily with unsaturated a ldehyde~ ,4~9~ ,~~ thus polyenoyl tetramic acid derivatives would be accessible by this approach. This paper describes the scope and limitations of this approach to the synthesis of functionalized tetramic acids.

Phosphonate-tetramic acid 7 was to be prepared by alkylation of isoxazole 10 followed by fragmentation of the resulting isoxazolium salt 9 to afford &keto amide 8. Previous studies by Rinehart; Mulholland,12 and Lacey13 had demonstrated that @-keto amides similar to 8 underwent base-catalyzed cyclization furnishing 3-acyltetramic acid derivatives.

Phosphonate 10 and phosphonium salt 12 were prepared as depicted in Scheme 11. Bromination of 5-methylisoxazole furnished 5-(bromomethyl)isoxazole (1 1) in 80% yield. Michaelis-Arbuzov reaction of bromide 11 with triethylphosphite yielded phosphonate 10. Alternatively, treatment of 11 with triphenylphosphine provided phosphonium salt 12. The insolubility of phosphonium salt 12

(12) Mulholland, T. P. C.; Foster, R.; Haydock, D. B. J. Chem. SOC.,

(13) Lacey, R. N. J. Chem. SOC. 1954, 850. Perkin Trans. 1 1972, 2121.

1358 J. Org. Chem., Vol. 53, No. 7, 1988 DeShong et al.

Table I. Wit t ig Reaction of Aldehydes with Phomhonate lO/PhosDhonium Salt 12 Wittig

entry aldehyde reagent yield isomer ratio

product (70)" ( E Z P

1 PhCHO

2 PhCHO

Me -CHO

3

4 Me =CHO

5

' . d C H O

13

6 13

14

8

M e 0 CHO

10

12

10

12

10

12

10

10

10

phyN 15A

15A:15B

16A

16A : 168

Me

17A

92 d

C 1.4:l.O

75 d

C 2.2: 1 .o

70 d

C 2.7:l.O

17A: 178

54 d

16 80 d

19

60 d

20

Yield of isolated, chromatographically homogeneous product. Determined by capillary gas chromatography or 'H NMR spectroscopy. CIsolated yield of mixture of alkenes was >60%. Optimized yields not determined. d E isomer exclusively.

in common organic solvents limited its application in the outlined approach, although it proved to be a viable Wittig olefination reagent (vide infra).

Olefination reactions of phosphonate 10 and phosphonium salt 12 were investigated and the results are sum- marized in Table I. For the condensation with phosphonate 10 and phosphonium salt 12, various base/solvent combinations were evaluated and the optimum conditions employed n-butyllithium in tetrahydrofuran. Aromatic aldehydes such as benzaldehyde and 3,4-dimethoxybenzaldehyde (entries 1, 2, and 8) and cr,P-unsaturated aldehydes (entries 3-7) were substrates in the olefination procedure. Even the extremely sensitive trans-retinal (14, entry 7) afforded an acceptable yield of homologated isoxazole (18) upon treatment with the phosphonate anion under optimum conditions. Also gratifying was the dis- covery that cyclohexanone (entry 9) was a viable substrate with the phosphonate reagent.

As anticipated, under these reaction conditions the condensation of aldehydes with the anion of phosphonate 10 furnished exclusively alkenes with the E configuration.14

The alkene geometry was confirmed from the 'H NMR spectra of the adducts which showed coupling constants of 15.2-16.4 Hz for the respective alkene resonances. This result was significant because the naturally occurring tetramic acid antibiotics always have the (E)-alkene configuration.

Representative olefinations with the ylide derived from phosphonium salt 12 afforded a mixture of (E)- and (2)-alkenes, with the E isomer predominating (Table I). Due to the disappointing lack of stereoselectivity observed in the reactions of the phosphorane, this coupling sequence was not investigated in detail.

Phosphonate 10 and related isoxazoles 15A and 21 were readily alkylated with electrophilic reagents to afford isoxazolium salts (Table 11). In each instance, treatment of the isoxazole with 1.1 equiv of the electrophile provided

(14) Boutagy, J.; Thomas, R. Chem. Rev. 1974,74,87. Wadsworth, W. S. Org. React. (N.Y.) 1977,25,73 and references cited therein. See also: Wittig, G.; Schollkopf, U. Chem. Ber. 1954,87, 1318. Schlosser, M. Top. Stereochem. 1970, 5, 1.

Synthesis of Tetramic Acid Derivatives J. Org. Chem., Vol. 53, No. 7, 1988 1359

Table 11. N-Alkylation o f Isoxazoles Scheme I11

electrophilic yield entry isoxazole reagent product (%)” Me

/ 1 M.

60 2 1

2 21

3 21

4 15A 5 15A

6 10 7 10

Me2S04

T10,,COOE1

2 3

Br,,COOEt, AgBF,

Me2S04 TIO,,COOEt

23

Me2S04 23

24

Me 6: x

~ C O O E t

25: X=TfO- 26: X=BF4-

27

4‘ N/+ TIO-

‘COOEt

28 29 30

TfO;, ‘COOEt

25 >95

N +

-CH ‘COOEt

L 39 40 1

complex mixture of Droducts

--

N,O-bond and afforded nitrilium ion 32. Subsequent capture of the nitrilium ion by water gave @-keto amide 33. Using a modified Woodward-Olofson protocol for isoxazolium salt fragmentation, @-keto amides were obtained from cleavage of the salts depicted in Table 11. In the modified protocol, a two-phase system of the isoxazolium salt in CHzClZ-Hz0 was treated with triethylamine to give the @-keto amides in excellent yield. For example, isoxazolium salt 24 was cleaved to afford a 90% yield of N-methylacetoacetamide.

R R

80

>95 > 95

J2 d 0

Et3N. H20, CHzCI2

0 ‘C

I \ MeSOT

>95 Me 2 4 : R = M e

> 95 Me

Yield of isolated product.

the corresponding salt in excellent yield. The salt was identified by its characteristic ‘H NMR spectrum in which the isoxazole proton signals a t 6 6.1 and 8.2 were shifted downfield to approximately 6 7.2 and 9.3, respectively, in the salt.

N-Methylation of isoxazoles 10, 15A, and 21 with neat dimethyl sulfate produced the respective isoxazolium salts in nearly quantitative yield. Similarly, treatment of these isoxazoles with carbethoxymethyl triflate (23) in nitromethane a t 0 OC according to the method of Vedejs15 afforded salts 25, 28, and 30, respectively (entries 2, 5, and 7). Alternatively, tetrafluoroborate salt 26 (entry 3) was prepared by alkylation of isoxazole 21 with ethyl bromoacetate in refluxing acetonitrile containing silver tetrafluoroborate; however, the harsh reaction conditions necessary to effect N-alkylation with the bromo ester limited the generality of this method. The isoxazolium salts were stable for weeks when stored a t 0 OC under an inert at- mosphere but underwent partial hydrolysis to give @-keto amides (vide infra) when exposed to adventitious moisture.

Me I MeS04- Me

31 32

I Me

33

Fragmentation of isoxazolium salt^ to yield &keto amide derivatives had been investigated previously by Woodward and Olofson.16 They demonstrated that deprotonation of isoxazolium salt 31 a t C-3 affected cleavage of the

(15) Vedejs, E.; Engler, D. A.; Mullins, M. J. J. Org. Chem. 1977, 42, 3109.

(16) Woodward, R. B.; Olofson, R. A. Tetrahedron, Suppl. 1966, 7, 415. Woodward, R. B.; Olofson, R. A. J. Am. Chem. SOC. 1961,83,1007. Woodward, R. B.; Olofaon, R. A.; Mayer, H. Ibid. 1961, 83, 1010.

27: R=CH=CHPh 34: R = Me 35: R=CH=CHPh 29: R=CHzPO(OEt)2 36: R=CH2PO(OEt)2

An anomalous product was obtained from the cleavage of isoxazolium salt 24 with triethylamine in tert-butyl alcohol. In the absence of a nucleophilic solvent, nitrilium ion 37A underwent head-to-tail dimerization to furnish cyclobutene 38 in 85% yield. The dimerization could have occurred by nucleophilic attack of the enolate of one molecule onto the nitrilium ion of the second. Alterna- tively, cyclobutene 38 may have arisen by [2 + 21 cyclo- addition of ketimine 37B.16

Me Mel I Me I O

24 L 37A 3 7 8 1 38

Carbethoxymethyl isoxazolium salts 25,26 ,28 , and 30 (Table 11), unlike the N-methyl analogues, were cleaved under basic conditions to provide an array of products from which the @-keto amide was not isolated. One possible explanation for this anomolous behavior is the presence of an electron-withdrawing group attached to the N-2 substituent of the salt. Under basic conditions, the kinetic acidity of the protons attached to C-1’ may be greater than C-3 and thus ylide formation (39/40) results either prior to or after isoxazolium ring fragmentation. The ylide must have reaction pathways available which are not common to the methyl isoxazolium fragmentation analogues (Scheme 111).

The failure of the fragmentation of isoxazolium salts 25, 26,28, and 30 to afford @-keto amides is a major limitation of this approach for the preparation of functionalized tetramic acids. For example, treatment of phosphonate 30 with 1 equiv of triethylamine in CH2C12-H,0 at 0 O C

followed by cyclization with sodium ethoxide in ethanol

1360 J. Org. Chem., Vol. 53, No. 7, 1988 DeShong et al.

of isoxazolium salt 31 afforded nitrilium salt 32 which, under anhydrous conditions, reacted with a-amino ester 45 to provide amidine 46. Subsequent base-catalyzed cyclization then afforded tetramic acid analogue, amidine 47. Hydrolysis of the amidine was expected to yield N-alkyltetramic acid 48.

In practice, this strategy was successful with simple isoxazole derivatives. For example, heating a solution of isoxazolium salt 24 and sarcosine ethyl ester (49) with potassium tert-butoxide in tert-butyl alcohol gave amidine 50A/50B in 55-60% yield. Amidine 50A was initially obtained along with its tautomer 50B. Recrystallization of the mixture from methanol afforded exclusively tautomer 50B.

Me

Scheme IV

Me MeS04-

31

0-

N + I b e

I- 32

R’

46

R‘

gave phosphonate-tetramic acid 41. However, the yield of tetramic acid was generally low (<20%) and irrepro- ducible.

h

f P(oE t’

1 NaHC03.CHzC12-H20

T+O- 2 NaOEt, EtOH

‘COOE,

30 0 II R*

A ’ R’

41: R ~ = H 43: R1=CH2Ph(OMe)2

42: R’=H 44:R’: CH2Ph(OMe)2

Disappointingly, attempts to condense anions derived from phosphonate 41 with aldehydes such as benzaldehyde, heptanal, and tiglaldehyde failed to afford tetramic acid derivatives under a variety of reaction conditions. Subsequent investigations in and Professor Schle~singer’s~ laboratory have indicated that the presence of a hydrogen atom on the tetramic acid nitrogen is re- sponsible for the unsatifactory condensation sequence. Replacement of the hydrogen of 41 by an alkyl group such as 3,4-dimethoxybenzyl gave a phosphonate derivative (43) which upon treatment with 2 equiv of potassium tert-butoxide according to the Schlessinger protocol5 condensed with aldehydes to furnish N-alkyltetramic acid 44.4b

The isoxazolium salt strategy outlined in Scheme I was not applicable to the preparation of N-alkyltetramic acid derivatives such as 43. Because the presence of an N-alkyl substituent was required for subsequent effective coupling of the tetramic acid derivatives, an alternative strategy was implemented (Scheme IV). Base-induced fragmentation

Me MeSOC

24

Me Me

Me Me Me 50A 50 B

The structure of the recrystallized tautomer was as- signed as 50B from spectral data. In particular, the ‘H NMR spectrum showed a one-proton, broad singlet a t 6 9.89 for the vinylogous amide proton, and a three-proton doublet at 6 3.20 with a coupling constant of 5.6 Hz for the N-methyl group.

Employing analogous methodology, the amidine analogue of erythroskyrine” (51) was prepared in 64% yield from isoxazolium salt 24 and L-valine ethyl ester, and amidine 52 was obtained in 60% yield from the reaction of 24 and N-benzylglycine ethyl ester. Interestingly, amidine 52 was isolated as the vinylogous amide tautomer 52B, whereas 51 was isolated in amidine form 51A.

#OH NMe e O H I NMe e ‘e,,. I I I I 8

H H Me En En Me

Reaction of the functionalized isoxazolium salts 27 and 29 with ethyl sarcosinate (49) under the basic conditions provided the amidines 53 and 54 in 60% and 55%, respectively. No tautomerization was noted in these sub- stances and the amidine was the sole product in each instance (Scheme V).

I t was anticipated that acid or base hydrolysis of the amidine moiety would provide the corresponding tetramic acid derivative. Close inspection of the literature, however, suggested that precautions had to be taken in this reaction because acid hydrolysis of 3-acyltetramic acid derivatives often resulted in liberation of the 3-acyl substituent.ls Indeed, hydrolysis of amidines 50A and 51-54 under a variety of acidic conditions failed to furnish the 3-acyl-

51 A 51 B 52 A 528

(17) Shoji, J.; Shibata, S.; Sankawa, U.; Taguchi, H.; Shibanuma, Y.

(18) Stickinga, C. E. Biochem. J. 1959, 72, 332. Chem. Pharm. Bull. (Tokyo) 1965, 13, 1240.

Synthesis of Tetramic Acid Derivatives J. Org. Chem., Vol. 53, No. 7, 1988 1361

Scheme V Ph

Ph I

Me Me

27 53

t

-- I M e S04-

Me Me \

29 54

tetramic acid derivative, respectively. Attempts to enhance hydrolysis of the amidine by initial

alkylation of the amidine with methyl fluorosulfonate followed by hydrolysis afforded complex reaction mixtures in which the desired tetramic acid (55) was not detected.

Me r M~ i Me

I Me Me

50A 55

The inability to affect hydrolysis of the amidine-tetramic acid derivatives meant that this promising strategy for the synthesis of 3-acyltetramic acid derivatives had t o be abandoned.

Experimental Section Melting points were taken in Kimax soft-glass capillary tubes

on a Thomas-Hoover Uni-Melt capillary melting point apparatus (Model 6406 K) equipped with a calibrated thermometer.

Proton magnetic resonance spectra ('H NMR) were recorded on a Bruker WP-200 or WM-360 Super Con spectrometer. Proton chemical shifts are reported in parts per million (6) downfield from tetramethyhilane. Coupling constants (J values) are given in hertz (Hz) and spin multiplicities are reported as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), b (broad). The deuteriated NMR solvent contained 99.0-99.8% deuterium in the indicated position. Infrared spectra were recorded on a Perkin- Elmer Model 281B diffraction grating spectrophotometer. Peak positions are given in reciprocal centimeters (cm-l) and are listed aswery strong (vs), strong (s), medium (m), weak (w), broad (b). Mass spectral data were obtained on a Kratos MS-950 double- focusing high-resolution spectrometer or on a Finnigan 3200 twin E1 and CI quadrupole mass spectrometer equipped with a Fin- nigan 6000 computer. The chemical ionization carrier gas was methane.

Thin-layer chromatography (TLC) was performed on 0.25-mm Merck silica gel coated glass plates with the compounds being identified in one or more of the following ways: UV light (254 nm), iodine, sulfuric acid, vanillin, ninhydrin, cerium(IV) sulfate, and/or molybdenum-phosphoric acid charring. Flash chromatography was performed on thick-walled glass columns and "medium pressure" silica gel (Merck 32-63 pm). The solvent systems used are reported in each experimental.

All solvents were distilled from CaC12 unless otherwise noted. Ethyl ether, benzene, and tetrahydrofuran were distilled from sodium/benzophenone ketyl. The reaction solvents (i.e., meth-

ylene chloride, toluene, carbon tetrachloride, nitromethane, and tert-butyl alcohol) were distilled from CaH2. n-Butyllithium was titrated against diphenylacetic acid (used as titrant and indicator) in THF a t 23 OC.19 All reactions were carried out in glassware that had been dried in an oven for a minimum of 8 h a t 120 "C and were assembled while hot under N2.

Preparat ion of 5-(Bromomethy1)isoxazole (1 1). N- Bromosuccinimide (2.14 g, 12.0 mmol) and freshly distilled 5- methylisoxazole (0.98 mL, 12 mmol) were combined in CC14 (30.0 mL) under NZ Benzoyl peroxide (0.291 g, 1.20 mmol) was added and the mixture was heated to 80 "C for 6 h. The reaction mixture was cooled to 0 OC and filtered, the filtrate was evaporated in vacuo, and the resultant residue was vacuum distilled to yield 1.55 g (80%) of 5-(bromomethyl)isoxazole (11) as a clear liquid: bp 58-62 "C/0.5 mm; IR (CC1,) 3135 (m), 2960 (m), 1780 (m), 1585 (s), 1460 (vs), 1420 (s), 1330 (vs), 1220 (vs), 1185 (vs), 1165 (vs) cm-';'H NMR (CDClJ 6 8.26 (b s, 1 H), 6.39 (b s, 1 H), 4.55 (8 , 2 H); mass spectrum, m / z (relative intensity) 163 (M', ll), 161 (M + 2, ll), 82 (loo), 40 (lo), 28 (16).

Preparation of Diethyl (5-Isoxazolylmethyl)phosphonate (10). Freshly distilled triethyl phosphite (3.40 mL, 19.8 mmol) was added to a stirred solution of 5-(bromomethyl)isoxazole (11) (3.21 g, 19.8 mmol) in 5.0 mL of toluene under N2 a t 0 "C. The reaction mixture was allowed to warm to room temperature over the course of 4 h and was then heated a t reflux for 24 h. After cooling, the solvent was evaporated in vacuo, and the resultant residue was vacuum distilled to yield 3.48 g (80%) of phosphonate 10 as a clear, viscous liquid bp 110-115 OC/0.35 mm; IR (CC14) 3150 (w), 2990 (vs), 2940 (s), 2910 (s), 1725 (s), 1595 (s), 1470 (vs), 1445 (s), 1395 (vs), 1370 (s), 1345 (s), 1270 (b vs), 1180 (s), 1160 (s), 1020 (b vs) cm-'; 'H NMR (CDC13) 6 8.27 (b s, 1 H), 6.33 (b s, 1 H), 4.17 (dq, J = 7.0, 7.0 Hz, 4 H), 3.45 (d, J = 21.4 Hz, 2 H), 1.36 (t, J = 7.0 Hz, 6 H); mass spectrum, m/z relative intensity) 219 (M', 31), 192 (44), 163 (42), 136 (23), 109 (loo), 83 (78).

P r e p a r a t i o n of (5-1soxazolylmethyl)triphenylphosphonium Bromide (12). Triphenylphosphine (1.58 g, 6.00 mmol) was dissolved in 15.0 mL of benzene under Nz. Bromo- isoxazole 11 (0.973 g, 6.00 mmol) dissolved in 3.0 mL of benzene was added to the phosphine solution and the reaction mixture was allowed to stir at 23 "C for 20 h. The reaction mixture was centrifuged and the solvent decanted leaving a light yellow solid. The solid was dispersed in CH2C12 and the centrifugation-de- cantation process was repeated until no color was evident in the CH2ClZ washings. Phosphonium bromide 12 (2.43 g, 95%) was obtained as a white solid: mp 225-226 "C; IR (Nujol) 2940-2880 (b vs), 2840 (vs), 1460 (s), 1360 (m), 1120 (w), 1080 (w) cm-'. Anal. Calcd for CzzHlgONPBr: C, 62.28; H, 4.51. Found: C, 61.98; H, 4.49.

General Procedure for the Horner-Emmons Olefinations with Phosphonate 10. Diethyl (5-isoxazolylmethy1)phosphonate (10, 1.0 equiv) was dissolved in THF (10 mL/mmol isoxazole) and cooled to 0 "C. Freshly titrated n-BuLi (1.5-2.5 M in hexanes, 1.0 equiv) was slowly added. Upon completion of addition, the neat aldehyde (1.1 equiv) was added. The reaction mixture was allowed to warm to 23 "C and was quenched by addition of H 2 0 after 5 h. The resultant solution WBS extracted thrice with CH2ClZ The extracts were combined, dried over anhydrous NaZSO4, and filtered, and the solvent was evaporated in vacuo. The resultant residue was purified by flash chromatography to give alkenes 15-20 in the indicated yields. (E)-5-(2-Phenylethenyl)isoxazole (15A) was prepared ac-

cording to the general procedure from isoxazole 10 (0.219 g, 1.00 mmol), n-BuLi (0.45 mL, 2.24 M, 1.0 mmol), and benzaldehyde (0.11 mL, 1.1 mmol) in 10 mL of THF. Flash chromatography with ethyl acetate-hexane (15) afforded 15A (Rf 0.36) as a yellow solid. Recrystallization from ethyl acetate-hexane gave 0.157 g (92%) of yellow needles: mp 33-34 OC; IR (CClJ 3160 (m), 3040 (s), 1950 (m), 1880 (m), 1810 (m), 1780 (m), 1745 (s), 1710 (s), 1645 (vs), 1470 (vs), 1350 (vs), 1170 (vs) cm-'; 'H NMR (CDC13) 6 8.20 (d, J = 1.8 Hz, 1 H), 7.50 (m, 2 H), 7.37 (m, 4 H), 6.98 (d, J = 16.4 Hz, 1 H), 6.25 (d, J = 1.8 Hz, 1 H); mass spectrum, m / t (relative intensity) 171 (M', 100), 144 (46), 103 (40), 77 (40). Anal. Calcd for CllHgNO: C, 77.17; H, 5.30. Found: C, 77.28; H, 5.61.

(19) Kofron, W. G.; Baclawski, L. M. J. Org. Chem. 1976, 41, 1879.

1362 J. Org. Chem., Vol. 53, No. 7, 1988

(E,E)-5-( 1,3-Pentadienyl)isoxazole (16A) was prepared according to the general procedure from isoxazole 10 (0.219 g, 1.00 mmol), n-BuLi (0.45 mL, 2.24 M, 1.0 mmol), and crotonaldehyde (0.090 mL, 1.1 mmol) in 10 mL of THF. Flash chromatography with CHzClz afforded 0.101 g (75%) of 16A (RfO.52) as a yellow oil: IR (CCl,) 3040 (s), 2980 (s), 2940 (s), 2860 (m), 1685 (m), 1650 (vs), 1465 (vs), 1450 (vs), 1350 (s), 1180 (s), 900 (s) cm-'; 'H NMR

1 H), 6.30 (d, J = 15.7 Hz, 1 H), 6.18 (m, 1 H), 6.11 (d, J = 1.7 Hz, 1 H), 5.99 (m, 1 H), 1.83 (d, J = 6.5 Hz, 3 H); mass spectrum, m/z (relative intensity) 135 (M", loo), 120 (E), 106 (54), 92 (14), 79 (87), 67 (38), 51 (25), 39 (66).

(E,E)-5-(3-Methyl-l,3-pentadienyl)isoxazole (17A) was prepared according to the general procedure from isoxazole 10 (0.219 g, 1.00 mmol), n-BuLi (0.45 mL, 2.24 M, 1.0 mmol), and tiglaldehyde (0.11 mL, 1.1 mmol) in 10 mL of THF. Flash chromatography with ethyl acetate-hexane (15) afforded 0.104 g (70%) of 17A (Rf 0.46) as a pale yellow oil: 'H NMR (CDCl,) 6 8.14 (d, J = 1.7 Hz, 1 H), 6.99 (d, J = 16.1 Hz, 1 H), 6.30 (d, J = 16.1 Hz, 1 H), 6.11 (d, J = 1.7 Hz, 1 H), 5.85 (m, 1 H), 1.78 (b s, 6 H); mass spectrum, m/z (relative intensity) 149 (M", 48), 137 (49), 122 (64), 106 (28), 94 (45), 79 (821, 66 (36), 53 (271, 43 (68), 28 (100). (aII-E)-5-[4,8-Dimethyl-lO-(2,6,6-trimethyl-l-cyclohexen-

1-yl)-1,3,5,7,9-decapentaenyl]isoxazole (18) was prepared according to the general procedure from isoxazole 10 (0.219 g, 1.00 mmol), n-BuLi (0.45 mL, 2.24 M, 1.0 mmol), and trans-retinal (14,0.313 g, 1.10 mmol) in 10 mL of THF. Flash chromatography with CHzClz afforded 18 (Rf 0.54) as an orange solid. Recrys- tallization from hexane gave 0.190 g (54%) of deep metallic orange crystals: mp 122-123 "C; IR (CC14) 3050 (s), 2970 (vs), 2930 (vs), 2870 (vs), 1625 (s), 1455 (vs), 1360 (s), 1150 (s) cm-'; UV (EtOH) 397 nm; 'H NMR (CDC13) 6 8.16 (d, J = 1.6 Hz, 1 H), 7.35 (dd, J = 15.2, 11.8 Hz, 1 H), 6.76 (dd, J = 15.2, 11.8 Hz, 1 H), 6.38 (m, 2 H), 6.16 (m, 5 H), 2.04 (s, 3 H), 1.97 (s, 3 H), 1.70 (s, 3 H), 1.59 (m, 4 H), 1.45 (m, 2 H), 1.01 (s, 6 H); mass spectrum, m / z (relative intensity) 349 (M", 100), 281 (15), 119 (26), 105 (25). Anal. Calcd for CZ,H,,NO: C, 82.48 H, 8.94. Found: C, 82.75; H, 9.29. (E)-5-[2-(3,4-Dimethoxyphenyl)ethenyl]isoxazole (19) was

prepared according to the general procedure from isoxazole 10 (0.219 g, 1.00 mmol), n-BuLi (0.45 mL, 2.24 M, 1.0 mmol), and 3,4-dimethoxybenzaldehyde (0.015 g, 0.090 mmol). Flash chromatography with CHzC12 afforded 19 (Rf 0.32) as a yellow solid. Recrystallization from ethyl acetate-hexane gave 0.185 g (80%) of 19 as white needles: mp 71-72 "C; IR (CC1,) 2990 (w), 2940 (w), 2920 (w), 2820 (w), 1635 (m), 1575 (m), 1500 (m), 1455 (s), 1260 (vs), 1120 (s), 1010 (s) cm-'; 'H NMR (CDC1,) 6 8.21 (d, J = 1.7 Hz, 1 H), 7.28 (d, J = 16.4 Hz, 1 H), 7.06 (m, 2 H), 6.86 (d, J = 8.1 Hz, 1 H), 6.85 (d, J = 16.4 Hz, 1 H), 6.22 (d, J = 1.7 Hz, 1 H), 3.39 (s, 3 H), 3.90 (s, 3 H); mass spectrum, m/z (relative intensity) 231 (M", loo), 216 (7), 191 (6), 161 (6).

5-(Cyclohexylidenemethyl)isoxazole (20) was prepared according to the general procedure from isoxazole 10 (0.219 g, 1.00 mmol), n-BuLi (0.45 mL, 2.24 M, 1.0 mmol), and cyclohexanone (0.11 mL, 1.1 mmol) in 10 mL of THF. Flash chromatography with CHZCIz afforded 0.0978 g (60%) of 20 (Rf 0.52) as a yellow oil: IR (CCl,) 2940 (vs), 2860 (vs), 1660 (vs), 1465 (vs), 1450 (vs), 1380 (s), 1345 (s), 1170 (s), 900 (s) cm-'; 'H NMR (CDC1,) 6 8.11 (s, 1 H), 6.06 (s, 1 H), 6.01 (s, 1 H), 2.60 (m, 2 H), 2.27 (m, 2 H), 1.64 (m, 6 H); mass spectrum, m / z (relative intensity) 163 (M", 39), 96 (loo), 81 (33).

General Procedure for the Wittig Olefinations with Triphenylphosphonium Bromide 12. The procedure is identical with that for the olefinations with phosphonate 10 (preceding section). After workup, TLC inspection of the reaction residue showed two overlapping spots, one corresponding to the E isomer, the other being the 2 isomer. Column chromatography of the residue failed to completely separate the mixtures. GC analysis of the fractions obtained from chromatography enabled deter- mination of the relative amount of each isomer present when correlated to TLC.

(2)-5-( 2-Phenyletheny1)isoxazole (15B) was prepared as a mixture with E isomer 15A according to the general procedure from isoxazole 12 (0.426 g, 1.00 mmol), n-BuLi (0.47 mL, 2.14 M, 1.0 mmol), and benzaldehyde (0.11 mL, 1.0 mmol) in 10 mL of THF. Examination of the reaction mixture by GC indicated the

(CDCl3) 6 8.15 (d, J = 1.7 Hz, 1 H), 6.93 (dd, J = 15.7, 10.3 Hz,

DeShong e t al.

E2 isomer ratio to be 1.4:l.O. A pure sample of the 2 isomer was isolated by flash chromatography with ethyl acetate-hexane (15): IR (CC1,) 3140 (w), 3050 (s), 3020 (s), 1945 (m), 1875 (w), 1800 (m), 1780 (m), 1635 (vs), 1455 (vs), 1340 (vs) cm-'; 'H NMR (CDCl,) 6 8.11 (b s, 1 H), 7.37 (m, 5 H), 6.91 (d, J = 12.4 Hz, 1 H), 6.55 (d, J = 12.4 Hz, 1 H), 6.01 (b s, 1 H); mass spectrum, m/z (relative intensity) 171 (M', 62), 131 (loo), 103 (54), 77 (32).

(E,Z)-5-( 1,3-Pentadienyl)isoxazole (16B) was prepared as a mixture with the E,E isomer 16A according to the general procedure from isoxazole 12 and crotonaldehyde. Examination of the reaction mixture by GC indicated the ratio of 16A:16B was 2.2:l.O. A pure sample of 16B could not be obtained.

(E,Z)-5-(3-Methyl-l,3-pentadienyl)isoxazole (17B) was prepared as a mixture with the E,E isomer 17A according to the general procedure from isoxazole 12 and tiglaldehyde. Exami- nation of the reaction mixture by GC indicated the ratio of 17A:17B was 2.7:l.O. A pure sample of 17B could not be obtained.

CAUTION! N-Alkylation of Isoxazoles May Result in Explosive Mixtures! Previous studies by Woodward and Olofson'6 indicated that N-alkylation reactions of isoxazoles had the propensity to detonate when heated too quickly. While our experiments never produced explosions (even when the reactions were performed neat), it is necessary to mention that use of the stronger methylating reagent, "Magic Methyl" (methyl fluorosulfonate) produced a vigorous, exothermic reaction. The methylating agent must be added dropwise to avoid overheating the reaction mixture.

Preparation of 2,5-Dimethylisoxazolium Methyl Sulfate (24). 5-Methylisoxazole (21, 8.65 mL, 106 mmol) and freshly distilled dimethyl sulfate (10.00 mL, 106 mmol) were combined neat under Nz. The mixture was slowly heated to 60 "C. After 2 h a t 60 "C, the reaction was heated to 80 "C for 5 h. The resultant liquid residue (22.17 g, 100%) did not require further purification and could be stored under Nz at 0 "C for weeks without undergoing significant decomposition: IR (neat) 3110 (s), 3040 (s), 2940 (m), 1600 (s), 1540 (vs), 1460 (s), 1310 (b vs), 1040 (vs), 990 (vs) cm-'; 'H NMR (CDCl,) 6 9.45 (d, J = 2.5 Hz, 1 H), 6.88 (d, J = 2.5 Hz, 1 H), 4.28 (s, 3 H), 3.40 (s, 3 H), 2.52 (s ,3 H). Due to the low volatility of the salt, mass spectral data could not be obtained.

Preparation of 2-Methyl-(E)-5-(2-phenylethenyl)isoxazolium Methyl Sulfate (27). (E)-5-(2-Phenylethenyl)isoxazole (15A) (0.171 g, 1.00 mmol) was dissolved in 1.0 mL of THF under Nz. Dimethyl sulfate (9.5 mL, 100 mmol) was added and the mixture was gradually heated to 60 "C and held at that temperature for 8 h. After cooling, the solvent was evaporated in vacuo and the resultant yellow semisolid (0.297 g, 100%) did not require further purification and could be stored under Nz at 0 "C for weeks without undergoing significant decomposition: IR (CCl,) 2940-2880 (b vs), 2840 (b vs), 1630 (w), 1575 (w), 1515 (w), 1460 (s), 1365 (m) cm-'; 'H NMR (CDClJ 6 9.53 (b s, 1 H), 7.55 (m, 3 H), 7.29 (m, 4 H), 7.04 (d, J = 16.8 Hz, 1 H), 4.44 (b s, 3 H), 3.66 (s, 3 H). Due to the low volatility of the salt, mass spectral data could not be obtained.

P repa ra t ion of 5-[(Diethoxyphosphinyl)methyl]-2- methylisoxazolium Methyl Sulfate (29). Isoxazole 10 (1.25 g, 5.70 mmol) and dimethyl sulfate (0.54 mL, 5.7 mmol) were combined neat under Nz. The mixture was gradually heated to 60 "C and held at that temperature for 8 h. The resultant residue (1.97 g, 100%) did not require further purification and could be stored under N2 at 0 "C for weeks without undergoing significant decomposition: IR (CC14) 2960 (s), 2910 (s), 2840 (s), 1740 (w), 1670 (w), 1460 (m), 1435 (m), 1395 (m), 1380 (m), 1230 (s), 1175 (s), 1090 (s), 1005 (s) cm-'; 'H NMR (CDCl,) 6 9.74 (d, J = 2.5 Hz, 1 H), 7.10 (d, J = 2.5 Hz, 1 H), 4.43 (b s, 3 H), 4.10 (dq, J = 7.0, 7.0 Hz, 4 H), 3.64 (d, J = 21.7 Hz, 2 H), 3.65 (b s, 3 H), 1.26 (t, J = 7.0 Hz, 6 H). Due to the low volatility of the salt, mass spectral data could not be obtained.

General Procedures for the Preparation of 2-(2-Ethoxy- 2-oxoethyl)isoxazolium Trifluoromethyl Sulfates. Freshly distilled trifluoromethanesulfonic acid (1.0 equiv) was dissolved in nitromethane (0.3 mL/mmol) under Nz at 0 "C. Ethyl diazoacetate (1.0 equiv) was slowly added dropwise to this solution. After addition was complete, the reaction mixture was allowed to stir for 1 h at 0 "C until N2 evolution had ceased. In a separate flask, the isoxazole (1.0 equiv) was dissolved in nitromethane (0.2

Synthesis of Tetramic Acid Derivatives

mL/mmol), cooled to 0 "C, and then transferred by cannula into the cold triflate solution. The resultant solution was allowed to stir for 15 h while warming to 23 OC. Removal of the solvent in vacuo gave the crude isoxazolium salt which did not require further purification and could be stored under Nz a t 0 "C for weeks without undergoing significant decomposition. Due to the low volatility of the salts, mass spectral data could not be obtained.

2-(2-Ethoxy-2-oxoet hyl)-5-met hylisoxazolium trifluoromethyl sulfate (25) was prepared according to the general procedure from trifluoromethanesulfonic acid (0.16 mL, 1.8 mmol), ethyl diazoacetate (0.19 mL, 1.8 mmol), and 5-methylisoxazole (0.15 mL, 1.8 mmol) in 0.9 mL of nitromethane. Evaporation of the solvent in vacuo gave isoxazolium salt 25 (0.575 g, 100%) as a pale yellow oil: IR (CCl,) 2970 (w), 1760 (b s), 1120 (s) cm-'; 'H NMR (CDC13) 6 9.47 (b s, 1 H), 7.01 (b s, 1 H), 5.60 (s, 2 H), 4.27 (q, J = 7.2 Hz, 2 H), 2.72 (s, 3 H), 1.29 (t, J = 7.2 Hz, 3 H).

2- (2-Ethoxy-2-oxoethy1)- (E)-5- (2-phenylet heny1)isoxazolium trifluoromethyl sulfate (28) was prepared according to the general procedure from trifluoromethanesulfonic acid (0.16 mL, 1.8 mmol), ethyl diazoacetate (0.19 mL, 1.8 mmol), and isoxazole 15A (0.308 g, 1.8 mmol) in 0.9 mL of nitromethane. Evaporation of the solvent in vacuo gave isoxazolium salt 28 (0.733 g, 100%) as a pale yellow oil: IR (CCl,) 3150 (vs), 2950 (b vs), 1760 (vs), 1630 (s), 1460 (s), 1360 (vs) cm-'; 'H NMR (CDC1,) 6 9.43 (d, J = 2.6 Hz, 1 H), 7.71 (d, J = 16.8 Hz, 1 H), 7.57 (m, 1 H), 7.39 (m, 4 H), 7.21 (d, J = 2.6 Hz, 1 H), 7.04 (d, J = 16.8 Hz, l H ) , 5 . 6 3 ( ~ , 2 H ) , 4 . 2 8 ( q , J = 7 . 1 H z , 2 H ) , 1 . 2 8 ( t , J = 7 . 1 H z , 3 H).

5-[ (Diet hoxyphosphiny1)met hyll-2- (2-ethoxy-2-oxo- ethy1)isoxazolium trifluoromethyl sulfate (30) was prepared according to the general procedure from trifluoromethanesulfonic acid (0.16 mL, 1.8 mmol), ethyl diazoacetate (0.19 mL, 1.8 mmol), and isoxazole 10 (0.395 mL, 1.8 mmol) in 0.9 mL of nitromethane. Evaporation of the solvent in vacuo gave isoxazolium salt 30 (0.820 g, 100%) as a pale yellow oil: IR (CC,) 2960 (vs), 2920 (vs), 2860 (s), 1750 (vs), 1460 (s), 1375 (s), 1280 (s), 1130 (vs), 1010 (vs) cm-'; 'H NMR (CDCl,) 6 9.59 (b s, 1 H), 7.17 (b s, 1 H), 5.62 (s, 2 H), 4.14 (m, 6 H), 3.67 (d, J = 21.3 Hz, 2 H), 1.30 (t, J = 7.0 Hz, 9 H). 2-(Carbethoxymethyl)-5-methylisoxazolium Tetra-

fluoroborate (26). Ethyl bromoacetate (1.67 g, 10.0 mmol) and 5-methylisoxazole (0.831 g, 10.0 mmol) were combined in the presence of silver tetrafluoroborate (2.14 g, 11.0 mmol) in a nitromethane solution and heated to 75 "C for 3 h. Filtration of silver bromide and evaporation of the solvent at reduced pressure gave 2.44 g (95%) of tetrafluoroborate salt 26 as a gum: IR (CHZC1,) 3140 (m), 2900 (w), 1755 (vs), 1590 (d), 1520 (s) 1325 (m), 1140-980 (br, vs) cm-'; 'H NMR (CDC1,) 6 9.22 (br, 1 H), 7.04 (br s, 1 H), 5.50 (s, 2 H), 4.27 (4, J = 7.0 Hz, 2 H), 2.70 (s, 3 H), 1.29 (t, J = 7.0 Hz, 3 H).

General Procedure for the Fragmentation of Isoxazolium Salts. The N-substituted isoxazolium salt (1.0 equiv) was stirred with CHzClz (2 mL/mmol isoxazolium salt) and HzO (1 mL/mmol isoxazolium salt) a t 23 "C under Nz. Triethylamine (1.0 equiv) was added and the two-phase system was stirred vigorously for 5 h. The layers were separated (except for 34, as noted) and the aqueous layer was extracted with CH2Clz (3 X ' / z aqueous volume). The combined organic layers were dried over anhydrous NaZSO4 and filtered, and the solvent was evaporated in vacuo. The resultant residue was chromatographed on silica gel with the solvent system indicated for each compound. N-Methyl-3-oxobutanamide (34) was prepared according to

the general procedure from isoxzolium methyl sulfate 24 (0.523 g, 2.50 mmol), triethylamine (0.35 mL, 2.5 mmol), 5.0 mL of CH2Clz, and 2.5 mL of H20. Due to the high solubility of the product in HzO, the entire reaction mixture was evaporated in vacuo and the residue was chromatographed with CH2Clz-MeOH (181) to yield 0.273 g (95%) of 34 (Rf 0.36) as a clear liquid: IR (CC14) 3380 (w), 2940 (w), 1710 (s), 1680 (vs), 1500 (m), 1410 (m), 1350 (m) cm-'; 'H NMR (CDCI,) 6 3.35 (s, 2 H), 2.74 (d, J = 4.8 Hz, 3 H), 2.20 (s, 3 H); mass spectrum, m/z (relative intensity) 115 (M', 69), 73 (37), 58 (53), 43 (100). (E)-N-Methyl-3-0~0-5-phenyl-4-pentenamide (35) was

prepared according to the general procedure from isoxazolium salt 27 (0.743 g, 2.50 mmol), triethylamine (0.35 mL, 2.5 mmol), 5.0 mL of CHZClz, and 2.5 mL of HzO. Flash chromatography

J. Org. Chem., Vol. 53, No. 7, 1988 1363

with CHzClz-MeOH (201) afforded 35 (Rf 0.46) as a yellow solid. Recrystallization from MeOH gave 0.458 g (90%) of a yellow powder: mp 95-96 "C; IR (CC1,) 3480 (w), 3350 (b w), 2930 (m), 2860 (m), 1675 (vs), 1645 (vs), 1600 (b vs), 1445 (m), 1405 (m), 1250 (s), 1095 (s) cm-l; 'H NMR (CDC13) 6 7.61 (m, 3 H), 7.37 (m, 3 H), 6.77 (d, J = 16.2 Hz, 1 H), 3.65 (s, 2 H), 2.84 (d, J = 4.7 Hz, 3 H); mass spectrum, m / t (relative intensity) 203 (M+, 32), 173 (8), 145 (19), 131 (loo), 103 (42), 77 (26).

Diethyl [4-(methylamino)-2,4-dioxobutyl]phosphonate (36) was prepared according to the general procedure from isoxazolium salt 29 (0.863 g, 2.50 mmol), triethylamine (0.35 mL, 2.5 mmol), 5.0 mL of CHzClz, and 2.5 mL of HzO. Flash chromatography with CH,Cl,-MeOH (153) yielded 0.558 g (89%) of 36 (Rf 0.40) as a clear, viscous liquid: IR (CCl,) 3460 (w), 3300 (m), 2970 (s), 1740 (m), 1715 (s), 1675 (vs), 1645 (s), 164C-1605 (b m), 1410 (m), 1385 (m) cm-'; 'H NMR (CDCI,) 6 7.14 (b s, 1 H), 4.04 (dq, J = 7.1, 7.1 Hz, 4 H), 3.50 (s, 2 H), 3.19 (d, J = 22.5 Hz, 2 H), 2.71 (d, J = 4.8 Hz, 3 H), 1.25 (t, J = 7.1 Hz, 6 H); mass spectrum, m/z (relative intensity) 251 (M', 83), 221 (34), 194 (79), 179 (80), 152 (67), 123 (loo), 109 (66).

Preparation of (E)-l,l'-[2-(Methylamino)-4-(methylimino)-l-cyclobutene-1,3-diyl]bis[ethanone] (38). Isoxazolium methyl sulfate 24 (0.418 g, 2.00 mmol) was dissolved in 4 mL of t-BuOH under NP. Triethylamine (0.28 mL, 2.0 mmol) was added and the mixture was stirred for 5 h. The solvent was evaporated in vacuo and the residue was chromatographed with CHZClz- MeOH (20:l) to give a dark yellow solid (Rf 0.41) which was recrystallized from ethyl acetate-hexane to yield 0.165 g (85%) of 38 as beige needles: mp 173-174 "C; IR (CC14) 1645 (vs), 1625 (vs), 1400 (8) cm-'; 'H NMR (CDC13) 6 5.63 (s, 1 H), 3.39 (s, 3 H), 2.90 (d, J = 5.1 Hz, 3 H), 2.64 (s,3 H), 2.29 (s,3 H); mass spectrum, m / z (relative intensity) 194 (M+, 34), 179 (loo), 56 (26). Anal. Calcd for CI0Hl4O2N2: C, 61.84; H, 7.27. Found: C, 61.61; H, 7.24.

General Procedure for Preparation of Cyclic Amidines. The N-substituted ethyl ester derivative of the amino acid (2.0 equiv) was dissolved in distilled t-BuOH under N,. Highest yields were obtained when the reaction concentration was 0.030 M in isoxazolium salt. Therefore, 70% of the required amount of solvent was used to dissolve the amino acid derivative, and the remaining solvent was used to complete the transfer of the other reagents. Solid potassium tert-butoxide (t-BuOK, 3.0 equiv) was added to this solution. (When the hydrochloride salt of the amino acid was used, 4.0 equiv of t-BuOK were required). After 2 min, the isoxazolium salt (1.0 equiv) dissolved in t-BuOH was added and the reaction mixture was heated to 80 OC for 5 h. The reaction mixture was cooled to 23 "C and quenched by addition of H 2 0 (l/z reaction volume). The resultant solution was transferred to a separatory funnel and extracted with CHzClz (3 x l/z reaction volume). The extracts were combined, dried over anhydrous NaZSO4, filtered, and evaporated in vacuo. Chromatography of the residue in the solvent systems indicated gave the amidines. The amidines were usually visible on TLC as bright red spots after exposure to iodine vapors.

(E) -4 - ( l-Hydroxyethylidene)-l-methyl-5-(methylimino)-3-pyrrolidinone (50A) was prepared according to the general procedure from sarcosine ethyl ester hydrochloride (0.307 g, 2.00 mmol), t-BuOK (0.449 g, 4.00 mmol), and isoxazolium methyl sulfate 24 (0.209 g, 1.00 mmol) in 33 mL of t-BuOH. Flash chromatography with CH2Cl2-MeOH (19:l) afforded 0.101 g (60%) of 50 (Rf0.38) as a pale red oil. This reaction product was a mixture of tautomers 50A and 50B. Recrystallization from cold MeOH gave clear plates (mp 165-166 "C) of tautomer 50A (40% overall yield): IR (CC14) 2910 (w), 1755 (w), 1675 (m), 1610 (s), 1435 (w), 1410 (w) cm-'; 'H NMR (CDCl,) 6 9.89 (b s, 1 H), 3.74 (s,2 H), 3.26 (8, 3 H), 3.20 (d, J = 5.6 Hz, 3 H), 2.41 (s, 3 H); mass spectrum, m/z (relative intensity) 168 (M', 1001,153 (88),82 (66), 44 (48).

( E ) - 4 - ( l-Hydroxyethylidene)-2-isopropyl-5-(methylimino)-3-pyrrolidinone (51A) was prepared according to the general procedure from (S)-valine methyl ester hydrochloride

methyl sulfate 24 (0.209 g, 1.00 mmol) in 33 mL of t-BuOH. Flash chromatography with ethyl acetate-hexane (3:2) afforded 51A (Rf 0.30) as a white solid. Recrystallization from MeOH gave 0.135 g (64%) of white powder: mp 91-92 "C; IR (CClJ 3260 (w), 2950

(0.335 g, 2.00 m o l ) , t-BuOK (0.449 g, 4.00 m o l ) , and i s o x a ~ ~ l i ~ m

1364 J. Org. Chem. 1988,53, 1364-1367

(m), 1750 (vs), 1635 (vs) cm-'; 'H NMR (CDC13) 6 9.38 (b s ,1 H), 4.94 (s, 1 H), 3.95 (d, J = 4.0 Hz, 1 H), 3.01 (8, 3 H), 2.20 (m, 1 H), 2.11 (8, 3 H), 1.05 (d, J = 6.8 Hz, 3 H), 0.88 (d, J = 6.8 Hz, 3 H); mass spectrum, m/z (relative intensity) 196 (M', 74), 181 (51), 153 (loo), 82 (37). (E)-4-( l-Hydroxyethylidene)-5-(methylimino)-l-(phe-

nylmethyl)-3-pyrrolidinone (52A) was prepared according to the general procedure from N-benzylglycine ethyl ester (0.386 g, 2.00 mmol), t-BuOK (0.337 g, 3.00 mmol), and isoxazolium methyl sulfate 24 (0.209 g, 1.00 mmol) in 33 mL of t-BuOH. Flash chromatography with CH2C12-MeOH (15:l) afforded 0.146 g (60%) of 52B (Rf 0.47) as a pale red oil: IR (CC14) 3050 (w), 2980 (m), 1755 (w), 1680 (s), 1620 (w), 1420 (s), 1260 (vs) cm-'; 'H NMR (CDC13) d 10.12 (b s, 1 H), 7.29 (m, 5 H), 4.79 (8, 2 H), 3.77 (s, 2 H), 3.10 (d, J = 5.6 Hz, 3 H), 2.45 (s, 3 H); mass spectrum, m/z (relative intensity) 244 (M', 81), 91 (loo), 82 (40).

(E)-4-[ Hydroxy[ 1 (E)-2-phenylethenyl]methylene]- 1- methyl-5-(methylimino)-3-pyrrolidinone (53) was prepared according to the general procedure from sarcosine ethyl ester hydrochloride (0.307 g, 2.00 mmol), t-BuOK (0.449 g, 4.00 mmol), and isoxazolium methyl sulfate 27 (0.297 g, 1.00 mmol) in 33 mL of t-BuOH. Flash chromatography with CH2C12-MeOH (18:l) gave amidine 53 ( R 0.40) as a light red solid. Recrystallization from ethyl acetatdexane gave 0.154 g (60%) of a pink powder: mp 82-83 OC; IR (CC14) 3020 (w), 2900 (m), 1750 (vs), 1650 (s), 1600 (b vs), 1485 (vs), 1390 (s), 1080 (vs) cm-'; 'H NMR (CDCI3)

6 7.52 (m, 3 H), 7.35 (m, 3 H), 6.82 (d, J = 15.9 Hz, 1 H), 4.96 (s, 1 H), 4.02 (8, 2 H), 3.30 (8, 3 H), 3.10 (8 , 3 H); mass spectrum, m/z (relative intensity) 265 (M', 100), 239 (26), 165 (12), 153 (32), 82 (59).

Diethyl (E)-[Z-hydroxy-2-[l-methyl-2-(methylimin0)-4- oxo-3-pyrrolidinylidene]ethyl]phosphonate (54) was prepared according to the general procedure from sarcosine ethyl ester hydrochloride (0.307 g, 2.00 mmol), t-BuOK (0.449 g, 4.00 mmol), and isoxazolium methyl sulfate 29 (0.345 g, 1.00 mmol) in 33 mL of t-BuOH. Flash chromatography with CH2C12-MeOH (9:l) afforded 0.167 g (55%) of 54 (R, 0.47) as a light yellow oil: IR (CC14) 2970 (m), 2910 (m), 1750 (s), 1645 (s), 1615 (s), 1495 (s), 1405 (s), 1225 (s), 1005 (s) cm-'; 'H NMR (CDCl,) 6 4.79 (s, 1 H), 3.96 (dq, J = 7.0, 7.0 Hz, 4 H), 3.84 (s, 2 H), 3.06 (b s, 3 H), 2.88 (s,3 H), 2.83 (d, J = 22.0 Hz, 2 H), 1.15 (t, J = 7.0 Hz, 6 H); mass spectrum, m/z (relative intensity) 304 (M', 15), 290 (8), 153 (loo), 126 (62), 82 (39).

Acknowledgment. We thank the National Institutes of Health (AI 20066 and 23688) and the Research Corpo- ration for generous financial support. We also thank Dr. Robert Minard (MS), Greg Hancock (MS), Alan Freyer (NMR), and Dr. Varadaraj Elango (NMR) for help in obtaining spectral data, and Robert Waltermire, Dr. Grady Lamb, and Dr. V. Elango for helpful discussions.

A New Stereoselective Method of Synthesis of Pyrrolizidines and Indolizidines'

Tatsuya Shono,* Naoki Kise, and Takayoshi Tanabe

Department of Synthetic Chemistry, Faculty of Engineering, Kyoto University, Yoshida, Sakyo, Kyoto 606, Japan

Received February 3, 1987

The addition of electrogenerated dichloro(methoxycarbny1)methyl anions to some N-(methoxycarbony1)-a-amino aldehydes prepared from a-amino acids was found to show about 100% diastereoselectivity. Some alkaloid-type compounds containing pyrrolizidine and indolizidine skeletons were synthesized from the adducts.

Recently we have found an anionic chain reaction induced by cathodic reduction.2 In this reaction, electro- geaerated trichloromethyl or dichloro(methoxy- carbony1)methyl (DMM) anion attacks an aldehyde to give l,l,l-trichloro-2-alkanol 1 or methyl 2,2-dichloro-3- hydroxyalkanoate 2 in a high current efficiency and a good yield. We have also reported the diastereoselective addition of these anions to a-branching aldehydes (eq 1)3 and

syn O P t l

1 Y=C!

2 Y=COOCH3

the application of the adducts to the stereoselective elon- gation of carbohydrate^.^^^ We report herein the stereoselective addition of the electrogenerated DMM anion to N-(carbomethoxy)-a-amino aldehydes 4 and the application of this reaction to the stereoselective synthesis of some

(1) Electroorganic Chemistry. 100. (2) Shono, T.; Kise, N.; Masuda, M.; Suzumoto, T. J. Ore. Chem. 1985,

50, 2521.

259. (3) Shono, T.; Kise, N.; Suzumoto, T. J. Am. Chem. SOC. 1984, 106 ,

(4) Shono, T.; Ohmizu, H.; Kise, N. Tetrahedron Lett. 1982,23,4801.

Table I. Yields of 5 and 6 and Isomeric Ratios of 6 6 5 3

R1 R, yield (%la yield (%Ib trans/cisC a 4CHzh- 66 68 >99/1

39 74 >99/ 1

C 50 54 >99/1 -(CH2)4- d (CH3)zCH H 46 65 >99/1

CH2CHCH2 -( e (CH3)&HCH2 H 40 66 87/13 f CBH,CHZ H 40 68 60/40 g P - C H ~ O C ~ H ~ C H ~ H 44 65 57/43

Isolated yield from 3. *Isolated yield from 5. See ref 6.

optically active compounds containing a pyrrolizidine or indolizidine skeleton. Although a number of methods for the synthesis of racemic pyrrolizidine and indolizidine derivatives have already been reportad, only a few methods have been known for the practical synthesis of optically active ones.5

(5) Some recent reports synthesizing optically active pyrrolizidine and indolizidine alkaloids are as follows. (a) Hart, D. J.; Yang, T. J . Org. Chem. 1985,50, 235. (b) Adams, C. E.; Walker, F. J.; Sharpless, K. B. Ibid. 1985,50,420. (c) Chamberlin, A. R.; Chung, J. Y. L. Ibid. 1985,50, 4425. (d) Nishiyama, Y.; Kondo, S.; Umezawa, H. Ibid. 1985,50, 5210.

0022-3263/88/1953-1364$01.50/0 0 1988 American Chemical Society

a general method for the synthesis of tetramic acid derivatives

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